Phosphonylated derivatives of aliphatic heterochain and acrylate polymers and applications thereof

ABSTRACT

A variety of phosphonylated heterochain polymers are disclosed, including, most preferably, phosphonylated polymethyl methacrylate. For each polymeric composition the phosphorous atom of a phosphorous-containing functional group is covalently bonded to a carbon atom of the polymeric chain. The phosphorous atoms are present in an amount of at least about 0.1 percent by weight in each polymeric composition.

This application is a division of U.S. Ser. No. 09/464,870 filed Dec.16, 1999 now U.S. Pat. No. 6,395,259, which claims benefit ofProvisional Application Ser. No. 60/116,408 filed Jan. 19, 1999.

BACKGROUND OF THE INVENTION

Phosphonylation of organic compounds and polymers has been documented inthe prior art. Early applications focused on mass phosphonylation ofnon-functional polymers to introduce phosphonylate groups randomly alongtheir carbon chain by allowing a solution of these polymers inphosphorous trichloride to interact with gaseous oxygen (U.S. Pat. No.3,097,194; U.S. Pat. No. 3,278,464). For example, U.S. Pat No. 3,097,194to Leonard is directed to a process for preparing elastomericphosphonylated amorphous copolymers of ethylene and propylene which areessentially free of low molecular weight polymer oils. Phosphorylation,or esterification of the copolymer, is conducted in situ of thecopolymer solution mass after inactivating a polymerization catalystwith water and oxygen to convert the catalyst to an inert metal oxide.Oxygen is then bubbled through the reaction mass in the presence ofphosphorous trichloride to obtain the phosphorylated copolymer.

An example of phosphonated polymers is provided in U.S. Pat. No.3,278,464 to Boyer et al. In accordance therewith, ethylenicallyunsaturated polymers are reacted with an organic-substituted phosphorouscompound to produce phosphonated polymers. Like the process describedabove, attachment of the phosphorous groups results in near-homogeneous,or mass, phosphonylation within the polymer and phosphorous compoundsare combined in a solvent system.

Moreover, in U.S. Pat. No. 4,207,405 to Masler et al., polyphosphatesare provided that are the homogeneous reaction products, in an organicsolvent, of phosphorous acid or phosphorous trichloride and awater-soluble carboxyl polymer. U.S. Nat. No. 3,069,372 to Schroeder etal., U.S. Pat. No. 4,678,840 to Fong et al., U.S. Pat. No. 4,774,262 toBlanquet et al., U.S. Pat. No. 4,581,415 to Boyle Jr., et al., and U.S.Pat. No. 4,500,684 to Tucker show various phosphorous-containing polymercompounds. U.S. Pat. Nos. 4,814,423 and 4,966,934 to Huang et al.,describe adhesives for bonding polymeric materials to the collagen andcalcium of teeth. For bonding to calcium, the adhesive employs anethylenically unsaturated polymeric monophosphate component. A tooth iscoated with the adhesive and then a filling is applied.

More recently, restricting the phosphonylation to the surface ofpolymeric substrates was achieved to produce articles withsurface-phosphonylate functionalities and practically intact bulk (U.S.Pat. Nos. 5,491,198 and 5,558,517 to Shalaby et al.). This was achievedby gas phase phosphonylation of a preformed article with PCl₃ and O₂ orpassing through a solution of PCl₃ in a non-reactive organic liquid thatis also a non-solvent for the polymeric article. In effect, a processfor phosphonylating the surface of an organic polymeric preform and thesurface-phosphonylated preforms produced thereby are provided. Organicpolymeric preforms made from various polymers including polyethylene,polyether-ether ketone, polypropylene, polymethyl methacrylate,polyamides and polyester, and formed into blocks, films, and fibers mayhave their surfaces phosphonylated according to that process. Theprocess involves the use of a liquid medium that does not dissolve thisorganic polymeric preform but does dissolve a phosphorous halide such asphosphorous trichloride, and the like. The process allows for surfacephosphonylation of the organic polymeric preform such that up to about30 percent but preferably up to about 20 percent, of the reactive carbonsites in the polymer are phosphonylated. The phosphonylated organicpolymers are particularly useful as orthopedic implants becausehydroxyapatite-like surfaces which can be subsequently created on theorganic implants allow for co-crystallization of hydroxyapatite to formchemically bound layers between prosthesis and bone tissue.

Although various phosphonylated polymers are known, the prior art isdeficient in affording phosphorous-containing groups randomly andcovalently attached to carbon atoms of aliphatic chains and pendant sidegroups of organo-soluble polymers such as polyalkylene oxides,polyamides, polyesters, and acrylate polymers, that are tailored for usein specified technology areas.

SUMMARY OF THE INVENTION

In one aspect the present invention is directed to a randomlyphosphonylated acrylate polymeric composition which includes an acrylicpolymer and phosphorous-containing functional groups, wherein thephosphorous atom of each functional group is covalently bonded to acarbon atom of the acrylic polymer and wherein the phosphorous atomscomprise at least about 0.1 percent by weight of the polymericcomposition.

Preferably, the acrylic polymer is polymethyl-methacrylate and thephosphorous atoms comprise at least 0.5 percent by weight of thepolymeric composition. Optionally, the acrylic polymer is based onmethyl-methacrylate and methacrylic acid repeat units. It is also withinthe scope of the present invention that the acrylic polymer includes atleast one polymerizable side group per chain, preferably a group derivedfrom a bis-acrylate monomer, most preferably, ethylene bis-methacrylate.

A preferred application for the phosphonylated acrylate polymericcomposition of the present invention is as a dental product such as avarnish or sealer, preferably one which includes fluoride ions which maybe released on a controlled manner. It is also desirable that the dentalproduct made in accordance with the present invention includes bioactivecompounds such as antimicrobials, anti-inflammatory drugs, orpain-relieving agents, with the polymeric composition being capable ofregulating the release of the bioactive compounds.

In another aspect the present invention is directed to a randomlyphosphonylated polyalkylene oxide polymeric composition which includes apolyalkylene oxide polymer and phosphorous-containing functional groups,wherein the phosphorous atom of each of the functional groups iscovalently bonded to a carbon atom of the polyalkylene oxide polymer andwherein the phosphorous atoms comprise at least about 0.1 percent byweight of the polymeric composition. Preferably the alkylene group ofthe polyalkylene oxide polymer has from two to six carbon atoms.

In yet another aspect the present invention is directed to a randomlyphosphonylated polyamide composition which includes a polyamide polymerand phosphorous-containing functional groups, wherein the phosphorousatom of each of the functional groups is covalently bonded to a carbonatom of the polyamide polymer and wherein the phosphorous atoms compriseat least about 0.1 percent by weight of the composition. Preferably, thepolyamide is the polymerization product of N-alkyl laurolactam.

In a still further aspect the present invention is directed to arandomly phosphonylated polyester composition which includes a polyesterpolymer and phosphorous-containing functional groups, wherein thephosphorous atom of each of the functional groups is covalently bondedto a carbon atom of the polyester polymer and wherein the phosphorousatoms comprise at least about 0.1 percent by weight of the composition.Preferably the polyester is poly-ε-caprolactone. The present polyestercomposition is especially useful as a flame retardant additive forpolyesters and polyurethanes.

All of the present inventive polymeric compositions may include abioactive compound linked to the phosphonyl functionality.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention deals with novel phosphonylated derivatives ofpolyalkylene oxides, N-substituted aliphatic polyamides, and acrylatepolymers, and preferably, specifically, polyethylene oxide (PEO),N-ethyl, Nylon 12 (N-12) [description of alkylated N-12 can be found inShalaby et al., J. Polym. Sci.-Polym. Phys. Ed., 11,1 (1973)], andpolymethyl methacrylate (PMMA). Generally, the phosphonylation of therepresentative members of these groups of polymers occurs by bubblingoxygen through a polymer solution in PCl₃ with or without a non-reactiveorganic solvent. The resulting phosphonyldihalide-bearing polymers maythen be converted to corresponding phosphonic acid and its metal salts,amides, imides, or esters. Conversion to (1) phosphonic acid is achievedby reacting with water in the presence or absence of an acidic or basiccatalyst (followed by acidification); (2) amides by reacting with anamine; (3) imides by reacting with a primary or secondary amide (as inthe case of the sodium salt of ε-caprolactam); and (4) esters byreacting with an alcohol or phenol.

A preferred composition of the present invention is a phosphonylatedPMMA having more than 0.1 percent phosphorous, present as phosphonicacid functionality, with the phosphonic acid being the dominantphosphonyl functionality. Another preferred composition of thisinvention is a derivative of the phosphonylated PMMA wherein the methylester groups of PMMA are partially or fully hydrolyzed [that take placeduring the hydrolysis of —P(O)Cl₂ to P(O)(OH)₂] are reacted (esterified)with a glycidyl acrylate (such as glycidyl methacrylate) to introduce apolymerizable acrylic side group onto the phosphonylated PMMA (PPMMA)chain. Another preferred composition of this invention is the reactionproduct of the PMMA [through the —P(O)Cl₂ functionality] withhydroxyethyl methacrylate (through the —OH group) to yield a product(PMH) having a phosphonate ester side group with a polymerizable acrylicfunctionality. Another preferred composition of this invention is aphosphonylated polyethylene oxide (OPPO) having more than 0.1 percentphosphorous present primarily as phosphonic acid groups, phosphonyldichloride and their respective derivative with hydroxy- oramine-bearing bioactive compounds. Another preferred composition of thisinvention is a phosphonylated N-alkylated Nylon 12 and more preferablyN-ethyl Nylon 12 having more than 0.1 percent phosphorous presentprimarily as phosphonic acid. Another preferred composition of thisinvention is a derivative of the phosphonylated N-ethyl Nylon-12,wherein the initial phosphonyl dihalide groups are reacted with sodiumε-caprolactam [using a similar process to that described by Shalaby andReimschuessel, J. Polym. Sci.-Polym. Chem. Ed., 15, 251 (1977)]. Anotherpreferred composition of this invention is phosphonylated polyester andmore preferably poly-ε-caprolactone having more than 0.1 percent P asfree phosphonic acid or dialkyl phosphonate groups. The latter can beprepared by reacting the initial phosphonylation product bearingphosphonyl dihalide groups with an alcohol such as ethanol or methanol.

Of the many possible applications of the new compositions subject ofthis invention, the following are representative systems:

1. Phosphonylated PMMA and Derivatives—These can be used in severaldental applications pertinent to (a) desensitizing through interactionwith Ca⁺² in the biologic environment to seal the teeth surface and fillthe micro-channel with an insoluble polymeric salt; (b) increasing theimpact strength of dental fillers through ionic binding of the polymericchain that acts as an impact modifier; (c) increasing the impactstrength of cement ionomers through the ionic binding of the impactmodifying polymer; (d) pretreating the surface of dentine for improvedadhesion to dental filling; (e) surface-coating to provide an adherentdental varnish or a controlled release system for fluorides and otherdental agents for treating infections (including microbial ones) orpain; and (f) interfacial-bonding of phosphonylated fibers to amethacrylate-based matrix for producing high impact dental composites.

2. Phosphonylated Polyethylene Oxides (PEO) and Derivatives—These can beused as drug carriers in different controlled release systems, such asthose used in transdermal delivery with or without employing aniontophoretic scheme. Other uses of the PEO phosphonic acid derivativescan include those pertinent to cold sterilization and disinfection.

Phosphonylated derivatives bearing phosphonyl dihalide groups can beused for covalently binding hydroxy- and/or amine-bearing bioactivecompounds for their controlled release. Yet another application ofphosphonic acid derivatives include their use as polyelectrolytes forflocculation. The phosphonic acid-bearing system can be used as acarrier of cationic drugs for controlling their release in oral,intranasal, intravaginal, or transdermal pharmaceutical formulations.The phosphonylated PEO can be used as a foam for protecting flammableobjects exposed to an open flame.

3. Phosphonylated N-ethyl Nylon 12 and Derivatives—N-ethyl Nylon 12 withpractically all the phosphonyl moieties present as phosphonic acidgroups can be used as polymeric catalysts for the hydrolyticpolymerization of lactams. The derivatives of the phosphonylated polymercarrying N-substituted ε-caprolactam group can be used as a co-catalystfor the anionic polymerization of lactams into comb-shaped orcrosslinked structures.

4. Phosphonylated Poly-ε-Caprolactone and Its Derivatives—These can beused as primers for metallic fibers in polymeric composite applications.The alkyl-phosphonate groups can be used as flame-retarding additivesfor polyesters and polyurethanes.

Specific examples for the preparation of representative compositions aregiven below.

EXAMPLE 1 Phosphonylation of Low Molecular Weight PolymethylMethacrylate

A two-neck 250 ml boiling flask containing a magnetic stir bar wasassembled with a condenser in one inlet and a gas inlet tube in theother. The set up was flame dried under vacuum and cooled to roomtemperature under argon purge twice. Twenty grams of low molecularweight polymethyl methacrylate (PMMA) and 50 ml chloroform was added tothe boiling flask. Once the PMMA was completely dissolved, 20 mlphosphorus trichloride was added to the solution. Oxygen was bubbledthrough the solution at 30 ml/min while stirring with the magnetic stirbar. The oxygen flow and stirring were continued at ambient temperaturefor 73 hours.

The condenser and gas inlet tube were removed from the flask andreplaced with a full length glass stopper and 90° angle connector withstopcock. The system was placed under vacuum while stirring to removethe chloroform. Once the solvent was removed, the flask was purged flaskwith argon and 100 ml acetone was added to dissolve the material in theflask. After the residue was dissolved, 37 ml of 0.5 M HCl was added tothe solution. After 48 hours, the solution was precipitated by blendingin distilled ice water for 2 minutes. The precipitate was collected byfiltering through a coarse Buchner funnel.

The precipitate was added to 500 ml distilled water and sonicated for 1hour. The mixture was filtered through a coarse Buchner funnel, and theprecipitate was collected. The precipitate was mixed with 250 mldistilled water and incubated at 37° C. for 1 hour. The water wasdecanted water, 250 ml distilled water was added, and the mixture wasincubated at 37° C. for 1 hour; repeated fifteen times. The mixture wasfiltered through a coarse Buchner funnel. The precipitate was collectedand dried under vacuum at 37° C. for 12 hours. The composition andproperties of the polymer were determined by elemental analysis, dilutesolution viscometry, titration, NMR, and IR spectroscopy.

EXAMPLE 2 Phosphonylation of Medium Molecular Weight PMMA

A two-neck 250 ml boiling flask containing a magnetic stir bar wasassembled with a condenser in one inlet and a gas inlet tube in theother. The set up was flame dried under vacuum and cooled to roomtemperature under argon purge twice. Twenty grams of medium molecularweight PMMA and 100 ml chloroform was added to the boiling flask. Oncethe PMMA was completely dissolved, 20 ml phosphorus trichloride wasadded to the solution. Oxygen was bubbled through the solution at 30ml/min while stirring with the magnetic stir bar. The oxygen flow andstirring were continued at ambient temperature for 91 hours.

The condenser and gas inlet tube were removed from the flask andreplaced with a full length glass stopper and 90° angle connector withstopcock. The system was placed under vacuum while stirring to removethe chloroform. Once the solvent was removed, the flask was purged flaskwith argon and 100 ml acetone was added to dissolve the material in theflask. The solution was precipitated by blending in distilled ice waterfor 2 minutes. The precipitate was collected by filtering through acoarse Buchner funnel.

The precipitate was mixed with 250 ml distilled water and incubated at37° C. for 1 hour. The water was decanted water, 250 ml distilled waterwas added, and the mixture was incubated at 37° C. for 1 hour; repeatedtwenty-three times. The mixture was filtered through a coarse Buchnerfunnel. The precipitate was collected and dried under vacuum at 37° C.for 12 hours. The composition and properties of the polymer weredetermined as described in Example 1.

EXAMPLES 3-23

Twenty additional phosphonylated PMMA derivatives are prepared usingsimilar or slightly modified reaction conditions and characterizationmethods as those described in Examples 1 and 2. A summary of theprevailing reaction conditions and analysis (for % P) of the productsare presented in Table I.

TABLE I Reaction Conditions and Properties of Resulting Products ProductPCl₃ Rxn Example Number PMMA** Solvent (ml) Time (hr.) % P  1 PM-9 20 gLow MW 50 ml chloroform 20 73 1.45  2 PM-10 20 g Medium MW 100 mlchloroform 20 91 1.88  3* PM-1 5 g Medium MW 15 ml chloroform 5 21 6.24 4* PM-2 S-1 5 g Medium MW Chloroform 10 16 2.19  5* PM-2 S-2 5 g MediumMW Chloroform 10 16 4.21  6* PM-3 10 g Medium MW 24 ml chloroform 10 272.77  7* PM-5 5 g Medium MW 25 methylene chloride 5 28 2.07  8 PM-6 Lot1 10 g Low MW 50 ml methylene chloride 10 26 1.48  9 PM-6 Lot 2 10 g LowMW 50 ml methylene chloride 20 24 1.35 10 PM-7 20 g Low MW 50 mlmethylene chloride 20 40 1.31 11 PM-8 20 g Medium MW 100 ml methylenechloride 20 48 1.54 12 PM-11 40 g Low MW 100 ml chloroform 40 47.5 0.5213 PM-12 40 g Medium MW 200 ml chloroform 40 94 1.14 14 PM-13 40 g LowMW 100 ml chloroform 40 99 1.34 15 PM-14 40 g 120K MW 125 ml chloroform40 42 1.32 16 PM-15 60 g Low MW 150 ml methylene chloride 60 48 1.07 17PM-16 60 g High MW 200 ml chloroform 60 91.5 1.39 18 PM-17 Lot 1 10 gLow MW 25 ml chloroform 10 74 1.43 19 PM-17 Lot 2 30 g Low MW 75 mlchloroform 30 104 1.42 20 PM-18 Lot 1 120 g High MW 455 ml chloroform120 120 1.41 21 PM-19 Lot 1 10 g Low MW 25 ml chloroform 10 96 1.85 22PM-19 Lot 2 20 g Low MW 50 ml chloroform 20 105 1.41 23 PM-20 Lot 1 120g High MW 450 ml chloroform 120 96 1.45 *These samples were preparedwithout provision for condensing liquid vapors. **Low MW PMMA M_(w) =34,473 Medium MW PMMA M_(w) = 73,227 High MW PMMA M₂ = 427,150

EXAMPLE 24 Phosphonylated PMMA Reacted with Hydroxyethyl Methacrylate

A two-neck 250 ml boiling flask containing a magnetic stir bar wasassembled with a condenser in one inlet and a gas inlet tube in theother. The set up was flame dried under vacuum and cooled to roomtemperature under argon purge twice. Thirty grams of low molecularweight polymethyl methacrylate (PMMA) and 75 ml chloroform was added tothe boiling flask. Once the PMMA was completely dissolved, 15 mlphosphorus trichloride was added to the solution. Oxygen was bubbledthrough the solution at 30 ml/min while stirring with the magnetic stirbar. The oxygen flow and stirring were continued at ambient temperaturefor 71 hours.

The condenser and gas inlet tube were removed from the flask andreplaced with a full length glass stopper and distillation arm connectedto a collection flask. The system was placed under vacuum at 50° C.while stirring to remove the chloroform. Once the solvent was removed,the flask was purged flask with argon and 60 ml chloroform was added todissolve the material in the flask. After the residue was dissolved, 6.1ml 2-hydroxyethyl methacrylate was added to the solution. After 5 days,the solution was precipitated by blending in distilled ice water. Themixture was left to settle in beakers and the water was then decanted.The solid portion was then transferred to a 2 L resin kettle and placedunder vacuum to remove chloroform. The solid portion was rinsed severaltimes with distilled water through vacuum filtration. Collectedprecipitate and dried under vacuum at 37° C.

The product contained 1.30% phosphorus and 1.16% chlorine and had amolecular weight of 9,023.

EXAMPLE 25 Phosphonylated PMMA Reacted with Glycidyl Methacrylate

A two-neck 250 ml boiling flask containing a magnetic stir bar wasassembled with a 90° angle connector with stopcock. The set up was twiceflame dried under vacuum and cooled to room temperature under argonpurge. The following were then added to the flask: 5.0 g 2-butanol; 3.0g PM-14; 0.005 g 4-methoxyphenol; 0.0015 g1,4-diazabicyclo-[2,2,2]oxetane; 1.5 g glycidyl-methacrylate; 100 gethyl acetate; and 50 g methanol. A sample was removed for FTIR analysisprior to reacting. The mixture was then heated to 60° C. under positiveargon pressure for 48 hours.

The 90° angle connector with stopcock was removed from the flask andconnected to a distillation head and the assembly was heated to 70° C.under vacuum for 45 min. The remaining mixture was precipitated blendingin distilled ice water. The precipitate was collected by filteringthrough a coarse Buchner funnel.

EXAMPLE 26 Phosphonylated PMMA Reacted with Glycidylmethacrylate

A two-neck 250 ml boiling flask containing a magnetic stir bar wasassembled with a 90° angle connector with stopcock. The set up was twiceflame dried under vacuum and cooled to room temperature under argonpurge. The following were then added to the flask: 5.0 g 2-butanol; 3.0g PM-14; 0.005 g 4-methoxyphenol; 0.0015 g1,4-diazabicyclo-[2,2,2]oxtane; 1.5 g glycidylmethacrylate; 100 g ethylacetate; and 50 g methanol. A sample was removed for FTIR analysis priorto reacting. The mixture was then heated to 60° C. under positive argonpressure for 48 hours.

The 90° angle connector with stopcock was removed from the flask andconnected to a distillation head and the assembly was heated to 70° C.under vacuum for 45 min. The remaining mixture was precipitated byblending in distilled ice water. The precipitate was collected byfiltering through a coarse Buchner funnel.

EXAMPLE 27 Calcium Salt of Phosphonylated PMMA of Example 21

The preparation and characterization of the calcium salt (to simulatethe reaction of the PPMMA reaction with Ca⁺² in the biologicenvironment) can be summarized as follows: 2% of PPMMA of Example 21 wasdissolved in ethanol then centrifuged (solubility was about 47%) to theclear solution, 5 drops of a 1M CaCl₂ solution were added, theprecipitate was centrifuged and washed twice with ethanol, then dried byvacuum for 4 days. SEM/EDX analyses of the resulting microparticles wereperformed for Ca, P, O, C, Cl.

EXAMPLE 28 Preparation of Dental Varnish

A tooth varnish was prepared by mixing 1.186 ml of a 2.5 mg/ml solutionof a 75/25 methyl methacrylate-methacrylic acid copolymer (MMA/MAA) inethanol with 50 μl of 2.5 mg/ml solution of the PPMMA of Example 23 inethanol in a sterile centrifuge tube. To this, 4 μl of a 2.5 mg/mlsolution of chlorhexadine diacetate in ethanol was added to yield afinal concentration of 0.1 μg/15 μl.

EXAMPLE 29 Preparation of Dental Varnish

For this, a procedure similar to that used in Example 28 was followedwith the exception of substituting the 75/25 MMA/MAA copolymer with its67/33 analog to yield a final concentration of 3.75 μg/15 μl.

EXAMPLE 30 Coating of Porcelain and Bovine Teeth as Models for Dentine

Porcelain and precut, scoured teeth were sanded with a fine-grade sandpaper. Both substrates were rinsed thoroughly with isopropyl alcohol anddried at room temperature for 48 hours prior to use. Triplicate samplesof both porcelain or bovine teeth were then coated with the dentalvarnish of Examples 28 or 29 to reach the desired concentration.

EXAMPLE 31 Drug Release Evaluation of Coated Porcelain

Porcelain chips from Example 30 were coated with a formulation ofExample 28 and placed in separate glass vials with 1 ml of distilledwater. The containers were then capped and placed in a 37° C. incubator.Aliquots were taken at various periods of time and analyzed by HPLCusing a 20-80% acetonitrile gradient and a C18 column and UV detector(220 nm). After 30 hours of incubation at 37° C., a total of 0.6 μg or1.5% of the total drug loading was released.

EXAMPLE 32 Drug Release Evaluation of Coated Teeth

The bovine teeth described in Example 30, which were coated with theformulation of Example 29, were evaluated in a similar manner asdescribed in Example 31. The results indicate that 70% of the drug isreleased at 3 days.

The foregoing description of preferred embodiments of the invention hasbeen presented for illustration, and is not intended to be exhaustive.Modifications are possible in light of the above teachings or may beacquired from practice of the invention.

What is claimed is:
 1. A randomly phosphonylated polyalkylene oxidepolymer comprising phosphorous-containing functional groups, wherein thephosphorous atom of each of the functional groups is covalently bondedto a carbon atom of the polyalkylene oxide polymer and wherein thephosphorous atoms comprise at least about 0.1 percent by weight of thetotal polymer weight.
 2. The phosphonylated polyalkylene oxide polymerof claim 1 wherein the alkylene group comprises from two to six carbonatoms.
 3. The phosphonylated polyalkylene oxide polymer of claim 1further comprising a bioactive compound linked to thephosphorous-containing functional groups.
 4. The phosphonylatedpolyalkylene oxide polymer of claim 1 wherein the phosphorous atomscomprise at least 0.5 percent by weight of the total polymer weight.